Herpes simplex virus (HSV) infections pose a significant and clinically relevant health problem for individuals infected with HIV. Natural history studies indicate that HSV-2 can be isolated a median of 10% of days among HIV-infect individuals and that 21% of HIV-positive person shed HSV-2 on more than 25% of days. Clinical reactivations of HSV-2 may last for weeks, with antiviral resistance rapidly increasing. HIV-1 has been isolated in high titers and for prolonged periods in most genital herpetic lesions, increasing the exposure of infiltrating T cells to replicating HIV. In a preliminary, cross-sectional study among HIV-infected persons co-infected with HSV-2, the Investigator and his associates have shown that impaired CD8+ cytotoxic T-lymphocyte (CTL) responses are associated with more severe genital HSV disease. In this application, the Investigator proposes to characterize the mechanisms behind this observation and answer the question as to whether the decline of HSV CTL activity in HIV-infected persons related to clonal deletion of HSV-specific T cells or loss of function due to abnormalities in accessory cell function, cytokine secretion, or apoptosis. HSV-specific T cell clones (CD4+ and CD8+) will be obtained from PBMCs and lesions and evaluated during the course of infection to determine if persons who experience a decline in pCTL experience clonal deletion of HSV-specific CD4+ or CD8+ T cells. The role of cytokine dysfunction in those with decreased pCTL to HSV will be assessed, also. As clinically those who have frequent HSV-2 have been shown to have more frequent, the researchers will also determine whether a bystander effect is associated with frequent and severe HSV reactivations on other endogenous opportunistic pathogens, specifically CMV. In addition, they will conduct studies to determine whether those with frequent and severe HSV reactivations experience more rapid reduction in T cell immunity to CMV.
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